The challenges Tendinopathy a continuum The long and winding road A (very) brief history History - continued Tendon tissue model Collagen types

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1 The challenges Tendinopathy a continuum The journey and its utility Craig Purdam Head of Discipline Physical Therapies Tendinopathy is varied does not respond universally to a given intervention The clinical research literature is heavily biased towards degenerative Uni-modal approaches to management have limited success Pain mechanisms are poorly understood The long and winding road A (very) brief history Puddu 1976 degenerative not inflammatory- tendinosis Smart, Taunton Clement 1980/4 ing and Biomx factors Curwin and Stanish 1984 eccentric programs But some got worse! Williams 1986 description of PG changes Leadbetter 1992 tenocyte proliferation Approach to management - Proliferative ( itis ) & degenerative subtypes History - continued Tendon tissue model Khan and Cook grey scale ultrasound changes reflect histo-pathology Cook 2004 Sequence of pathological change Cook and Malliaris 2008, Visnes 2007 Longitudinal ultrasound changes Cook and Purdam 2009 Continuum hypothesis Collagen types I, III. Small amounts of V,VI XII, XIV Compression zones II, IX, X, XI Proteoglycans: decorin, aggrecan, versican,,biglycan, lumican, fibromodulin Glycoproteins: Fibronectin, Laminin Thrombospondin & COMP, Tenascin C Undulin, Fibrillin Growth factors and receptors TNFα, TGFβ, VEGF, PDGF, bfgf, IL1 β Mechanotransduction: Integrins, cadherins, connexins, actin and ion channels Tendon cells produce: Proteoglycans & Collagen Glutamate, Acetylcholine, Tyrosine Hydroxylase, TNF Matrix mediators Matrix metalloproteinases (MMPs), Tissue inhibitor of MMPs (TIMPs), ADAMTS Neuropeptides: Noradrenalin, NPY, Ach,VIP, SP, NKA, CGRP, Tyrosine hydroxylase, glutamate, galanin, somatostatin Picture: M Collins 1

2 Number of tendons 2/02/2011 Pathology Cells change Tendinosis Complete/partial tears Acute/chronic paratenonitis Mixed lesions Become active Rounder (chondroid) Increased cell numbers ground substance, collagen A feature of reactive/proliferative (Sensitised to ) Tnf α in horses and humans Or may burn out Decrease in cell numbers and cell death (apoptosis) A feature of degenerative Leadbetter 1992, Hosaka 2006 Normal Tenocyte proliferation Ground substance changes Large increases Change in major proteoglycan type from decorin to Aggrecan much larger MW Short half-life (3 days) Binds much more water in tendon => swelling Up to 25 X increase in synthesis and 5X increase in breakdown Entrapment of hydroxlated debris in matrix Handley, Simic 2008 Collagen changes Initial cleaving or separation of collagen bundles Later disorganisation and loss of larger diameter collagen with degenerative regions Vascularity changes Many new vessels generally originating from anterior interface Accompanied by neural ingrowth ( mostly autonomic) Relationship with tendon pain not absolute Nelen 1989, Williams 1986, Astrom 1994, Alfredson Figure: Ohberg Alfredson et al 2002 Sequence of pathological changes Combination of histopathological changes Tenocyte only Tenocyte & ground substance tenocyte, ground substance & collagen alteration Cook et al JOR 2004 tenocyte, ground substance, collagen alteration & vascularity Temporal arrangement Tenocytes affected first generally up-regulated but can also burn out Increase in ground substance Collagen disarray Neo-vascularisation Pathology can be nonuniform through tendon 2

3 Patellar Tendon status: month to month change over 6 months of volleyball training (aggregated) n=289 85% NORMAL Chart Title 13% 2% n=13 3 PROLIFERATIVE Proliferative 135 Chart Title 37% 47% 16% Malliaris & Cook 2006 DEGENERATIVE Degenerative 158 Chart Title 81% 16% 3% Normal or excessive +/- individual factors Tendinopathy Model Uned (sedentary, post surgical, pathological) Uned Optimised Normal tendon Excessive + individual factors Appropriate modified Reactive Tendon dysrepair Degenerative Optimised Load Strengthen Adaptation Cells activated proteoglycans cleave collagen As above & neurovascular ingrowth Cells degenerate, islands of matrix degeneration Cook & Purdam 2008 Summary of pathological model Progression of arthritis Tenocyte & cytokines(?) activation Matrix changes Collagen changes Neovascular changes Cell & collagen degeneration Reactive Dysrepair Degenerative Pollard et al 2008 Identifying the stage Clinical presentation Age/ Prevalence Younger, (15-25y), short term high Young athletes or a direct blow Older (20-35y) and/or ongoing More common Oldest (30-60y) and/or ongoing Common Pain??? Generally acute, some asymptomatic Sometimes Grumbling pain with episodes. May be painfree Palpation findings Fusiform swelling of tendon 3-4cm Fusiform swelling of tendon 3-4cm Variable swelling and lumps/bumps Tendon response Aggravated by exercise, slow to settle sensitised Active Attempting to heal Less irritable Often uning strategies or muscle atrophy., Less competent to deal with sport s/ 3

4 Diagnostic ultrasound provides stage of the condition - not function or pain!! Reactive Fusiform swelling in tendons without vessels Current thoughts on optimising conservative management Dysrepair swollen tendons with neurovascular changes Degenerative hypoechoic regions with localised degenerative patches and neurovascular changes Medical Interventions: principles Reduce the sensitisation of the tenocytes in acute/reactive phase Attempt to reduce large proteoglycan (Aggrecan) deposition Local interventions to the neurovascular in-growth/down regulate & remodel the matrix Medical interventions: Reactive Tenocyte inhibitors ibuprofen, celecoxib Tsai et al 2004, 2007 corticosteroids Fredberg 2004, Scutt 2006, but Bisset 2006!! Aggrecan inhibitors - ibuprofen, naproxen sodium, indomethacin Dingle 1999, Riley 2001 TNF α inhibitors? - doxycycline Fallon et al 2008, green tea Cao et al 2007 fish oil Mehra et al 2006 Triple therapy* Fallon et al 2008 Attempt to stimulate healing in degenerative phase Medical interventions: Dysrepair Polidocanyl (Alfredson 2005) TGFβ inhibitors - May be useful in long standing thickened tendon due to re modelling and reduction of fibrosis/scarring no research at present time on tendons (Peritendon stripping (Alfredson, Willberg 2010)) GTN patches? (Paoloni et al 2003,4 Murrell 2007) Autologous blood/platelet rich plasma? - PDGF, TGFβ1 VEGF Anitua et al 2004, Lee & Hamilton 2008 Medical interventions: Degenerative Autologous blood/platelet rich plasma - PDGF, TGFβ1 VEGF (Anitua et al 2004) Prolotherapy (Rabago et al 2005, Topol et al 2004, Taunton 2011) Stem Cells - equine only (+ 48 week rehab) (Smith 2008) GTN patches - (Paoloni et al 2003,4 Murrell 2007) Not corticosteroids! (Bissett et al 2006) Exercise is the most potent stimulus to remodel the matrix!!!! These may augment the process 4

5 Loading and rehabilitation principles Reactive Take longer to settle and progress, sensitised to over Initial bodyweight isometrics, then moderate to heavy s Load management and Return To Sport progression Dysrepair Address contractile deficits (muscle bulk) Graduate tendon more quickly determined by symptoms More formal structure and progression Then 3 day cycles (Hi Lo Med tendon days) Degenerative Address contractile deficits Graduate tendon - eccentric programs as indicated 3 day cycles (Hi Lo Med days) Determine ideal end-point Workshop Rehabilitation principles Loading progression Monitoring Maintenance Managing in-season Current perspective on interventions for long term recovery Medications 10% Biomechanical corrections 15-20% Modalities Appropriate and progression 60-70% Turtle juice Stretching and massage Summary: reactive tendons? - swollen, no holes, no vessels Uning training and biomechanical optimisation Tenocyte inhibitors Aggrecan inhibitors? Corticosteroid injections **Not ultrasound, ECSWT **Not frictions or eccentric/elastic ing Injections 10-15% Core strengthening Summary: degenerative tendons - swollen, nodular, holes, vessels Exercise, which may progress to include eccentric ing Sclerosing therapy Glyceryl trinitrate patches (with exercise) Ultrasound, ECSWT Prolotherapy if entheseal Surgery ** Not corticosteroids Looking forward Greater specificity of research cohorts eg Mahieu et al 2010 More effective means of settling activated tenocytes (without a downside) Understanding and optimising the tendon s adaptation to ing Understanding the pain of and respectful interventions 5

6 Questions and comments? 6